文章：

癌症中的多功能酶

multifunctional enzymes in cancer

原文发布日期：2006-10-01

DOI: 10.1038/nrc1949

类型: Review Article

开放获取: 否

要点：

1. There are 11 human cysteine cathepsins, which primarily function as endopeptidases within endolysosomal compartments. Specific cysteine cathepsins have extracellular functions, for example, cathepsin K in bone remodelling by osteoclasts.
2. Multiple mechanisms increase cysteine cathepsin expression in tumours, including amplification of the cathepsin B gene and alternative splicing of cathepsin L and B transcripts. Increases in expression occur both in tumour cells and tumour-associated cells such as macrophages, endothelial cells and myoepithelial cells.
3. In tumours these enzymes can be secreted, bind to specific regions on the cell membrane and are localized in endolysosomal vesicles. Their substrates and functions differ depending on their location.
4. Causal roles for cysteine cathepsins in cancer have been demonstrated by pharmacological and genetic techniques. This includes functional downregulation of cysteine cathepsin activity by increasing expression of endogenous inhibitors and administration of small-molecule cysteine protease inhibitors.
5. Causal roles for cysteine cathepsins in cancer have also been identified in regard to intracellular matrix degradation following endocytosis of collagens by urokinase plasminogen activator receptor-associated protein (uPARAP).
6. Causal roles for specific cysteine cathepsins in cancer have been demonstrated by downregulating their expression or crossing mouse models of cancer with mice in which the cysteine cathepsin has been genetically ablated. These studies have identified roles for cysteine cathepsins in both tumour cells and tumour-associated cells such as endothelial cells and macrophages.

要点翻译：

1. 人类共有11种半胱氨酸组织蛋白酶，它们主要作为内肽酶在内体溶酶体区室内发挥作用。特定的半胱氨酸组织蛋白酶具有细胞外功能，例如破骨细胞在骨重塑过程中分泌的组织蛋白酶K。
2. 多种机制可导致肿瘤中半胱氨酸组织蛋白酶表达增加，包括组织蛋白酶B基因的扩增以及组织蛋白酶L和B转录本的可变剪接。这种表达增加既发生在肿瘤细胞中，也见于肿瘤相关细胞（如巨噬细胞、内皮细胞和肌上皮细胞）。
3. 在肿瘤中，这些酶可被分泌至细胞外，与细胞膜特定区域结合，并定位于内体溶酶体囊泡中。其底物和作用会因定位不同而存在差异。
4. 通过药理学和遗传学技术已证实半胱氨酸组织蛋白酶在癌症中的因果作用，包括通过增加内源性抑制剂表达和给予小分子半胱氨酸蛋白酶抑制剂来实现功能性下调其活性。
5. 半胱氨酸组织蛋白酶在癌症中的因果作用还体现在尿激酶纤溶酶原激活物受体相关蛋白（uPARAP）介导的胶原内吞后发生的细胞内基质降解过程。
6. 通过下调特定半胱氨酸组织蛋白酶的表达，或将癌症小鼠模型与半胱氨酸组织蛋白酶基因敲除小鼠杂交，已证实特定半胱氨酸组织蛋白酶在癌症中的因果作用。这些研究揭示了半胱氨酸组织蛋白酶在肿瘤细胞及肿瘤相关细胞（如内皮细胞和巨噬细胞）中的作用。

英文摘要：

Cysteine cathepsins are highly upregulated in a wide variety of cancers by mechanisms ranging from gene amplification to post-transcriptional modification. Their localization within intracellular lysosomes often changes during neoplastic progression, resulting in secretion of both inactive and active forms and association with binding partners on the tumour cell surface. Secreted, cell-surface and intracellular cysteine cathepsins function in proteolytic pathways that increase neoplastic progression. Direct proof for causal roles in tumour growth, migration, invasion, angiogenesis and metastasis has been shown by downregulating or ablating the expression of individual cysteine cathepsins in tumour cells and in transgenic mouse models of human cancer.

摘要翻译： 

半胱氨酸组织蛋白酶在多种癌症中显著上调，其机制包括基因扩增及转录后修饰等。在肿瘤进展过程中，它们原本位于细胞内溶酶体的分布常发生改变，导致无活性和有活性的酶形式均被分泌，并与肿瘤细胞表面的结合伴侣相互作用。分泌型、细胞膜表面及细胞内的半胱氨酸组织蛋白酶通过蛋白水解途径促进肿瘤进展。通过在肿瘤细胞以及人癌转基因小鼠模型中下调或敲除单个半胱氨酸组织蛋白酶的表达，已直接证实其在肿瘤生长、迁移、侵袭、血管生成和转移中具有因果作用。

原文链接：

multifunctional enzymes in cancer